The use of HMG-COA reductase inhibitors for the reduction of serum cholesterol levels is well known. These compounds include alkyl esters of hydroxy substituted naphthalenes which are orally effective in the reduction of serum cholesterol levels. Examples of these compounds include mevastatin which is described in U.S. Pat. No. 3,671,523; lovastatin which is described in U.S. Pat. No. 4,231,938; pravastatin which is described in U.S. Pat. No. 4,346,227; and simvastatin which is described in U.S. Pat. No. 4,444,784. All of these patents are incorporated by reference.
Lovastatin is a metabolite which is produced by the natural fermentation of an fungus of the Aspergillus genus. Lovastatin acts systemically to lower blood serum cholesterol levels by disrupting the biosynthesis of cholesterol in the liver, where 70% to 80% of body cholesterol is produced. Specifically lovastatin interrupts a step in the endogenous production of cholesterol by inhibiting the HMG coenzyme A reductase from combining with bile acids in the digestive tract such that the bile acids are excreted from the body without reabsorption. With synthesis in the liver thusly inhibited, the liver cells must take cholesterol from the bloodstream, and they do so by increasing their production of cell surface receptors for LDL cholesterol. Lovastatin formulations are generally capable of lowering the blood serum cholesterol level by about 30-40%. The other compounds of this class are derived from natural or synthetic sources using well known procedures and have similar mechanisms of activity.
However, it is desirable to enhance the activity of these compounds to achieve even greater reductions of blood serum cholesterol levels in connection with the treatment of hypercholesterolemia and other maladies. Accordingly, the present invention provides a novel controlled release formulation of a compound which is an alkyl ester of a hydroxy substituted naphthalene derivative which provides for a gradual release of the compound. This formulation has been prepared to provide a slow controlled release of these compounds in order to provide a more constant level of bioavailability in order to provide an enhanced effect that cannot be achieved by conventional immediate release dosing. The use of a controlled release form of is believed to be specially useful for those who have meals at irregular times or those who frequently eat snacks between meals. These subjects include night shift workers, airline personnel and travelers, and those individuals with blood sugar problems who eat frequent small meals. In addition, it is believed that the human body synthesizes high amounts of cholesterol during the hours of sleep and it is desirable in certain cases to provide therapeutic level of these compounds during periods of sleep.
Controlled release formulations have been described in U.S. Pat. No. 4,615,698 which have been based on an osmotic dosage form which is designed to collapse and cause the faced surfaces to come into a close contacting arrangement as the drug is delivered through a passageway in the semi-permeable wall of the dosage form. In addition, U.S. Pat. No. 4,503,030 discloses an osmotic dosage form which has a passageway and a semi-permeable membrane consisting of a particular cellulose polymer and a pH-sensitive material which could be an enteric coating material. This patent describes the use of 1:1 mixtures of a pH sensitive material and cellulose polymer which are applied at a level of about 70% by weight based on the total weight of the osmotic core tablet and coating material.
In the parent application, the applicants have discovered that a ratio of 0.75:1, and lower, of pH sensitive material to cellulose polymer may be used to provide a stable membrane around an osmotic core tablet at a coating level of 1-4% by weight based on the total weight of the osmotic core tablet and coating material. These osmotic tablets will substantially, completely deliver the compound without the need to provide a passageway in the tablet according to the teachings of the prior art. In addition the osmotic tablet of the invention will provide higher bioavailability and lower peak plasma drug concentrations than are provided by the same weight of the alkyl ester of a hydroxy substituted naphthalene derivative in a conventional immediate release dosage form.